The goals are (1) to develop a more complete oxygen transport and metabolism model, namely, incorporating more general nonlinear binding of oxygen to hemoglobin and myoglobin, incorporating effect of pH and CO2, and incorporating mitochondria into our current nonlinear oxygen model; (2) to integrate the oxygen model with other models for substrate transport and metabolism and for cardiac energetics; and (3) to expand the applications of the oxygen model. The first goal requires better understanding of non-equilibrium binding of oxygen to hemoglobin and myoglobin under varied physiological conditions, the transport of CO2, and mitochondria distribution and kinetics. The second goal is for integrating specific blood-tissue exchange models at a higher level. Currently, we are developing a comprehensive model for cardiac purine metabolism. The integration of the oxygen model and the purine model, combining with a finite-element model for cardiac mechanics, will help the understanding of the relationships among cardiac substrate transport, ATP utilization, and cardiac contractile functions during different physiological and pathological conditions. For the third goal, we are ready for some simulation studies on the BOLD technique in which the non-equilibrium binding of oxygen to hemoglobin and myoglobin, and time-varying blood flow, blood volume and metabolic activity are accounted for in the oxygen model.